title: SC-514, a selective inhibitor of IKKβ attenuates RANKL-induced osteoclastogenesis and NF-κB activation.
abstract: The RANKL-induced NF-κB signaling pathway is essential for osteoclastogenesis. This study aims to identify specific inhibitors targeting NF-κB signaling pathway, which might serve as useful small molecule inhibitors for the treatment and alleviation of osteoclast-mediated bone lytic diseases. By screening for compounds that selectively inhibit RANKL-induced NF-κB activation in RAW264.7 cells as monitored by luciferase reporter gene assay, we identified SC-514, a specific inhibitor of IKKβ, as a candidate compound targeting osteoclastogenesis. SC-514 dose-dependently inhibits RANKL-induced osteoclastogenesis with an IC50 of <5μM. At high concentrations, SC-514 (≥12.5μM) induced apoptosis and caspase 3 activation in RAW264.7 cells. Moreover, SC-514 specifically suppressed NF-κB activity owing to delayed RANKL-induced degradation of IκBα and inhibition of p65 nuclear translocation. Taken together, our results indicate that SC-514 impairs RANKL-induced osteoclastogenesis and NF-κB activation. Thus, targeting IKKβ by SC-514 presents as a potential treatment for osteoclast-related disorders such as osteoporosis and cancer-induced bone loss.
authors.affiliation: Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi 530021, China; School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley 6009, Western Australia, Australia; Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Crawley 6009, Western Australia, Australia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Huafei
authors.initials: H
authors.lastname: Wu
authors.forename: Shek Man
authors.initials: SM
authors.lastname: Chim
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Jinmin
authors.initials: J
authors.lastname: Zhao
authors.forename: Haotian
authors.initials: H
authors.lastname: Feng
authors.forename: Qingli
authors.initials: Q
authors.lastname: Wei
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Ming H
authors.initials: MH
authors.lastname: Zheng
authors.forename: Ren Xiang
authors.initials: RX
authors.lastname: Tan
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gu
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Nathan
authors.initials: N
authors.lastname: Pavlos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tickner
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D053245:RANK Ligand / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D053245:RANK Ligand; C477523:SC 514; D013876:Thiophenes; C505689:Tnfsf11 protein, mouse; D051550:I-kappa B Kinase; D053148:Caspase 3
keywords: Bone marrow cells; NF-κB; Osteoclastogenesis; RANKL; SC-514